Immunoglobulin A Nephropathy: Molecular Pathogenesis and Targeted Therapy

Immunoglobulin A nephropathy (IgAN), the most prevalent primary glomerulonephritis globally, is characterized by mesangial IgA deposition and heterogeneous clinical trajectories. Historically, management relied on renin-angiotensin system inhibition and empirical immunosuppression, yet high lifetime kidney failure risk persists despite optimized care. This review synthesizes advances in molecular pathogenesis, highlighting how the traditional multi-hit hypothesis-while foundational for targeted therapy development-fails to capture IgAN's recurrent, self-amplifying nature. We introduce the "spiral hypothesis" as a dynamic model of cyclical immune-injury cascades, better explaining disease chronicity and necessitating sustained maintenance therapy. Emerging targeted therapies-including B-cell targeted agents (e.g., APRIL/BAFF inhibitors), complement inhibitors (e.g., iptacopan), and mucosal immunomodulators (e.g., TRF-budesonide)-enable early intervention addressing both upstream immunological drivers and downstream fibrotic pathways. We critically evaluate treat-to-target frameworks, defining remission endpoints (proteinuria <0.3 g/day, hematuria resolution, estimated glomerular filtration rate slope <-1 mL/min/year) and emphasizing biomarker-guided personalization. The paradigm shift toward proactive management prioritizes individualized therapeutic sequencing of novel agents based on dynamic risk stratification. Future priorities include optimizing protocols for high-risk phenotypes and refining long-term safety monitoring to ensure sustainable efficacy.